tbuckley/cabot-search huggingface dataset:
Evolution and Diversity of the TopoVI and TopoVI-like Subunits With Extensive Divergence of the TOPOVIBL subunit
Authors: Julia Brinkmeier, Susana Coelho, Bernard de Massy, Henri-Marc Bourbon
Journal: Molecular Biology and Evolution (2022)

Abstract Type II DNA topoisomerases regulate topology by double-stranded DNA cleavage and ligation. The TopoVI family of DNA topoisomerase, first identified and biochemically characterized in Archaea, represents, with TopoVIII and mini-A, the type IIB family. TopoVI has several intriguing features in terms of function and evolution. TopoVI has been identified in some eukaryotes, and a global view is lacking to understand its evolutionary pattern. In addition, in eukaryotes, the two TopoVI subunits (TopoVIA and TopoVIB) have been duplicated and have evolved to give rise to Spo11 and TopoVIBL, forming TopoVI-like (TopoVIL), a complex essential for generating DNA breaks that initiate homologous recombination during meiosis. TopoVIL is essential for sexual reproduction. How the TopoVI subunits have evolved to ensure this meiotic function is unclear. Here, we investigated the phylogenetic conservation of TopoVI and TopoVIL. We demonstrate that BIN4 and RHL1, potentially interacting with TopoVIB, have co-evolved with TopoVI. Based on model structures, this observation supports the hypothesis for a role of TopoVI in decatenation of replicated chromatids and predicts that in eukaryotes the TopoVI catalytic complex includes BIN4 and RHL1. For TopoVIL, the phylogenetic analysis of Spo11, which is highly conserved among Eukarya, highlighted a eukaryal-specific N-terminal domain that may be important for its regulation. Conversely, TopoVIBL was poorly conserved, giving rise to ATP hydrolysis-mutated or -truncated protein variants, or was undetected in some species. This remarkable plasticity of TopoVIBL provides important information for the activity and function of TopoVIL during meiosis.
USPSTF Recommendations on Vitamin and Mineral Supplements for Primary Prevention of Cardiovascular Disease and Cancer—Reply
Authors: Carol Mangione, Michael Barry, John Wong
Journal: JAMA (2022)

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Prevalence of Positive Rapid Antigen Tests After 7-Day Isolation Following SARS-CoV-2 Infection in College Athletes During Omicron Variant Predominance
Authors: Jessica Tsao, Andrea Kussman, Nicole A. Segovia, Geoffrey D. Abrams, Alexandria B. Boehm, Calvin E. Hwang
Journal: JAMA Network Open (2022)

Importance The US Centers for Disease Control and Prevention shortened the recommended isolation period for SARS-CoV-2 infection from 10 days to 5 days in December 2021. It is unknown whether an individual with the infection may still have a positive result to a rapid antigen test and potentially be contagious at the end of this shortened isolation period. Objective To estimate the proportion of individuals with SARS-CoV-2 infection whose rapid antigen test is still positive starting 7 days postdiagnosis. Design, Setting, and Participants This case series analyzed student athletes at a National Collegiate Athletic Association Division I university campus who tested positive for SARS-CoV-2 between January 3 and May 6, 2022. Individuals underwent rapid antigen testing starting 7 days postdiagnosis to determine whether they could end their isolation period. Exposures Rapid antigen testing 7 days after testing positive for SARS-CoV-2. Main Outcomes and Measures Rapid antigen test results, symptom status, and SARS-CoV-2 variant identification via campus wastewater analysis. Results A total of 264 student athletes (140 [53%] female; mean [SD] age, 20.1 [1.2] years; range, 18-25 years) representing 268 infections (177 [66%] symptomatic, 91 [34%] asymptomatic) were included in the study. Of the 248 infections in individuals who did a day 7 test, 67 (27%; 95% CI, 21%-33%) tests were still positive. Patients with symptomatic infections were significantly more likely to test positive on day 7 vs those who were asymptomatic (35%; 95% CI, 28%-43% vs 11%; 95% CI, 5%-18%; P &amp;amp;lt; .001). Patients with the BA.2 variant were also significantly more likely to test positive on day 7 compared with those with the BA.1 variant (40%; 95% CI, 29%-51% vs 21%; 95% CI, 15%-27%; P = .007). Conclusions and Relevance In this case series, rapid antigen tests remained positive in 27% of the individuals after 7 days of isolation, suggesting that the Centers for Disease Control and Prevention–recommended 5-day isolation period may be insufficient in preventing ongoing spread of disease. Further studies are needed to determine whether these findings are present in a more heterogeneous population and in subsequent variants.
Evaluation of Standard-of-Care Practices Among Physicians Who Treat Other Physicians
Authors: Anna McNair Avinger, Tekiah McClary, Margie Dixon, Rebecca D. Pentz
Journal: JAMA Network Open (2022)

Importance Ethical discussions have suggested that physicians who treat other physicians may put their physician-patients at risk of receiving non–standard-of-care treatment, which may result in worse outcomes. This phenomenon occurs when a physician treats a fellow physician as a VIP (very important person), and is therefore known as VIP syndrome . It is important to assess physicians’ perceptions when treating physician-patients. Objective To determine whether the physicians treating other physicians have attitudes toward or act in ways that could place physician-patients at risk for VIP syndrome. Design, Setting, and Participants This 2-part qualitative study was conducted from December 1, 2021, to February 28, 2022. Physicians who worked at a single comprehensive cancer center with experience treating other physicians were eligible to participate. Convenience sampling was used. Emails and flyers were sent out with study information, and if interested, physicians were able to schedule an interview. Of 24 physicians responding, 3 did not have experience treating other physicians, yielding a sample of 21 (88%), which was sufficient to reach a saturation of themes. After the initial structured interview of physicians, follow-up key informant interviews were performed. Exposures The structured interview was developed on the basis of a literature review and focused on factors that may contribute to VIP syndrome. Main Outcomes and Measures Participant responses to open-ended questions were qualitatively coded using standard multilevel semantic analysis to assess physician perceptions of treating fellow physicians. A series of Likert-scaled questions were used to identify potential contributing factors to VIP syndrome. Results Twenty-one physicians (11 men [52%], 11 White [52%], and 15 [71%] younger than 49 years) participated. Although no physician interviewed stated that they altered their usual treatment plans, 11 (52%) agreed that their physician-patients tried to dictate their own care, and 17 (81%) believed that their physician-patients obtained privileges, such as use of medical knowledge to participate in in-depth discussions of care, ability to obtain and use the treating physicians personal contact information, and receiving faster access to care. Eleven respondents (52%) reported increased stress, and 12 (57%) experienced more pressure not to disappoint their physician-patients. Conclusions and Relevance The findings of this qualitative study suggest that when physicians treat other physicians, the physician-patients may obtain privileges unavailable to patients who are not physicians. Therefore, guidelines to help physicians navigate the complex relationships between themselves and their physician-patients are needed to ensure equitable outcomes between physician and nonphysician patients.
Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors
Authors: Daniel Q. Huang, Philippe Mathurin, Helena Cortez-Pinto, Rohit Loomba
Journal: Nature Reviews Gastroenterology & Hepatology (2022)

Heavy alcohol consumption is a major cause of morbidity and mortality. Globally, alcohol per-capita consumption rose from 5.5 litres in 2005 to 6.4 litres in 2016 and is projected to increase further to 7.6 litres in 2030. In 2019, an estimated 25% of global cirrhosis deaths were associated with alcohol. The global estimated age-standardized death rate (ASDR) of alcohol-associated cirrhosis was 4.5 per 100,000 population, with the highest and lowest ASDR in Africa and the Western Pacific, respectively. The annual incidence of hepatocellular carcinoma (HCC) among patients with alcohol-associated cirrhosis ranged from 0.9% to 5.6%. Alcohol was associated with approximately one-fifth of global HCC-related deaths in 2019. Between 2012 and 2017, the global estimated ASDR for alcohol-associated cirrhosis declined, but the ASDR for alcohol-associated liver cancer increased. Measures are required to curb heavy alcohol consumption to reduce the burden of alcohol-associated cirrhosis and HCC. Degree of alcohol intake, sex, older age, obesity, type 2 diabetes mellitus, gut microbial dysbiosis and genetic variants are key factors in the development of alcohol-associated cirrhosis and HCC. In this Review, we discuss the global epidemiology, projections and risk factors for alcohol-associated cirrhosis and HCC.
COP27 climate change conference: urgent action needed for Africa and the world
Authors: Lukoye Atwoli, Gregory E Erhabor, Aiah A Gbakima, Abraham Haileamlak, Jean-Marie Kayembe Ntumba, James Kigera, Laurie Laybourn-Langton, Bob Mash, Joy Muhia, Fhumulani Mavis Mulaudzi, David Ofori-Adjei, Friday Okonofua, Arash Rashidian, Maha El-Adawy, Siaka Sidibé, Abdelmadjid Snouber, James Tumwine, Mohammad Sahar Yassien, Paul Yonga, Lilia Zakhama, Chris Zielinski
Journal: BMJ (2022)
Virological characteristics of the SARS-CoV-2 Omicron BA.2.75 variant
Authors: Akatsuki Saito, Tomokazu Tamura, Jiri Zahradnik, Sayaka Deguchi, Koshiro Tabata, Yuki Anraku, Izumi Kimura, Jumpei Ito, Daichi Yamasoba, Hesham Nasser, Mako Toyoda, Kayoko Nagata, Keiya Uriu, Yusuke Kosugi, Shigeru Fujita, Maya Shofa, MST Monira Begum, Ryo Shimizu, Yoshitaka Oda, Rigel Suzuki, Hayato Ito, Naganori Nao, Lei Wang, Masumi Tsuda, Kumiko Yoshimatsu, Jin Kuramochi, Shunsuke Kita, Kaori Sasaki-Tabata, Hideo Fukuhara, Katsumi Maenaka, Yuki Yamamoto, Tetsuharu Nagamoto, Hiroyuki Asakura, Mami Nagashima, Kenji Sadamasu, Kazuhisa Yoshimura, Takamasa Ueno, Gideon Schreiber, Akifumi Takaori-Kondo, Kotaro Shirakawa, Hirofumi Sawa, Takashi Irie, Takao Hashiguchi, Kazuo Takayama, Keita Matsuno, Shinya Tanaka, Terumasa Ikeda, Takasuke Fukuhara, Kei Sato
Journal: Cell Host & Microbe (2022)

The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically distinct from BA.5, the currently predominant BA.2 descendant. Here, we show that BA.2.75 has a greater effective reproduction number and different immunogenicity profile than BA.5. We determined the sensitivity of BA.2.75 to vaccinee and convalescent sera as well as a panel of clinically available antiviral drugs and antibodies. Antiviral drugs largely retained potency, but antibody sensitivity varied depending on several key BA.2.75-specific substitutions. The BA.2.75 spike exhibited a profoundly higher affinity for its human receptor, ACE2. Additionally, the fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were greater than those of BA.2. Our multilevel investigations suggest that BA.2.75 acquired virological properties independent of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5.
The Predictive Performance of Contemporary Guideline Recommendations for Helicobacter pylori Testing in a United States Population
Authors: Theresa Nguyen Wenker, Frederick B. Peng, Ikenna Emelogu, Niharika Mallepally, Fasiha Kanwal, Hashem B. El-Serag, Mimi C. Tan
Journal: Clinical Gastroenterology and Hepatology (2022)
Lineage-mosaic and mutation-patched spike proteins for broad-spectrum COVID-19 vaccine
Authors: Yangtao Wu, Shaojuan Wang, Yali Zhang, Lunzhi Yuan, Qingbing Zheng, Min Wei, Yang Shi, Zikang Wang, Jian Ma, Kai Wang, Meifeng Nie, Jin Xiao, Zehong Huang, Peiwen Chen, Huilin Guo, Miaolin Lan, Jingjing Xu, Wangheng Hou, Yunda Hong, Dabing Chen, Hui Sun, Hualong Xiong, Ming Zhou, Che Liu, Wenjie Guo, Huiyu Guo, Jiahua Gao, Congling Gan, Zhixiong Li, Haitao Zhang, Xinrui Wang, Shaowei Li, Tong Cheng, Qinjian Zhao, Yixin Chen, Ting Wu, Tianying Zhang, Jun Zhang, Hua Cao, Huachen Zhu, Quan Yuan, Yi Guan, Ningshao Xia
Journal: Cell Host & Microbe (2022)

SARS-CoV-2 spread in humans results in continuous emergence of new variants, highlighting the need for vaccines with broad-spectrum antigenic coverage. Using inter-lineage chimera and mutation-patch strategies, we engineered a recombinant monomeric spike variant (STFK1628x) that contains key regions and residues across multiple SAR-CoV-2 variants. STFK1628x demonstrated high immunogenicity and mutually complementary antigenicity to its prototypic form (STFK). In hamsters, a bivalent vaccine composed of STFK and STFK1628x elicited high titers of broad-spectrum neutralizing antibodies to 19 circulating SARS-CoV-2 variants, including Omicron sublineages BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.75, and BA.4/5. Furthermore, this vaccine conferred robust protection against intranasal challenges by either SARS-CoV-2 ancestral strain or immune-evasive Beta and Omicron BA.1. Strikingly, vaccination with the bivalent vaccine in hamsters effectively blocked within-cage virus transmission of ancestral SARS-CoV-2, Beta variant, and Omicron BA.1 to unvaccinated sentinels. Thus, our study provided insight and antigen candidates for the development of next-generation COVID-19 vaccines.
The Amyloid Inhibitor CLR01 Relieves Autophagy and Ameliorates Neuropathology in a Severe Lysosomal Storage Disease
Authors: Antonio Monaco, Veronica Maffia, Nicolina Cristina Sorrentino, Irene Sambri, Yulia Ezhova, Teresa Giuliano, Vincenzo Cacace, Edoardo Nusco, Maria De Risi, Elvira De Leonibus, Thomas Schrader, Frank-Gerrit Klärner, Gal Bitan, Alessandro Fraldi
Journal: Molecular Therapy (2022)

(Molecular Therapy 28, 1167–1176; April 2020) In the originally published version of this article, an error was made during the assembly of Figure 4A: the cropped image used as representative of "striatum anti-GFAP WT + saline" was inadvertently taken from the folder containing the cropped images of "striatum anti-GFAP WT + CLR01" fields, instead of from the correct folder (cropped images of “striatum anti-GFAP WT + saline” fields). Therefore, two partial overlapping cropped images of the same field (striatum anti-GFAP WT + CLR01) were used in the panel. The correct version of Figure 4A is included here. The authors apologize for the error. The Amyloid Inhibitor CLR01 Relieves Autophagy and Ameliorates Neuropathology in a Severe Lysosomal Storage DiseaseMonaco et al.Molecular TherapyFebruary 11, 2020In BriefFraldi and colleagues demonstrated that multiple amyloid proteins progressively aggregate in neurons of a severe lysosomal storage disease, impairing autophagy degradation and triggering neurodegeneration. They also showed that inhibiting amyloid deposition protects against neurodegeneration, thus providing evidence that amyloid aggregation is a new attractive target for the treatment of LSDs. Full-Text PDF Open Access
Benign Lobular Inner Nuclear Layer Proliferations of the Retina Associated with Congenital Hypertrophy of the Retinal Pigment Epithelium
Authors: Christian J. Sanfilippo, Michael Javaheri, Sheryl Handler, Jesse L. Berry, David Cobrinik, Matthew A. Deardorff, Miao Sun, Ryan J. Schmidt, Andrew J. Barkmeier, Aaron Nagiel
Journal: Ophthalmology (2022)
How collaboration between bioethicists and neuroscientists can advance research
Authors: Insoo Hyun, J. C. Scharf-Deering, Sarah Sullivan, John Dennis Aach, Paola Arlotta, Matthew L. Baum, George M. Church, Aaron Goldenberg, Henry T. Greely, Parastoo Khoshakhlagh, Richie E. Kohman, Melissa Lopes, Caroline Lowenthal, Aric Lu, Alex H. M. Ng, Sergiu P. Pasca, Bruna Paulsen, Martina Pigoni, Christopher T. Scott, David A. Silbersweig, Mark A. Skylar-Scott, Robert D. Truog, Jeantine E. Lunshof
Journal: Nature Neuroscience (2022)
Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy
Authors: Dominic Denk, Valentina Petrocelli, Claire Conche, Moritz Drachsler, Paul K. Ziegler, Angela Braun, Alena Kress, Adele M. Nicolas, Kathleen Mohs, Christoph Becker, Markus F. Neurath, Henner F. Farin, Christian J. Buchholz, Pénélope A. Andreux, Chris Rinsch, Florian R. Greten
Journal: Immunity (2022)

T memory stem cells (TSCM) display increased self-renewal and prolonged survival capabilities, thus preventing T cell exhaustion and promoting effective anti-tumor T cell responses. TSCM cells can be expanded by Urolithin A (UA), which is produced by the commensal gut microbiome from foods rich in ellagitannins and is known to improve mitochondrial health. Oral UA administration to tumor-bearing mice conferred strong anti-tumor CD8+ T cell immunity, whereas ex vivo UA pre-treated T cells displayed improved anti-tumor function upon adoptive cell transfer. UA-induced TSCM formation depended on Pink1-mediated mitophagy triggering cytosolic release of the mitochondrial phosphatase Pgam5. Cytosolic Pgam5 dephosphorylated β-catenin, which drove Wnt signaling and compensatory mitochondrial biogenesis. Collectively, we unravel a critical signaling pathway linking mitophagy to TSCM formation and suggest that the well-tolerated metabolic compound UA represents an attractive option to improve immune therapy.
Activating cGAS-STING pathway with ROS-responsive nanoparticles delivering a hybrid prodrug for enhanced chemo-immunotherapy
Authors: Lei Cao, Huixiang Tian, Man Fang, Zhe Xu, Dongsheng Tang, Juan Chen, Jiye Yin, Haihua Xiao, Kun Shang, Hongbin Han, Xiangping Li
Journal: Biomaterials (2022)

cGAS-STING pathway, as an essential intracellular immune response pathway, has attracted much attention in tumor immunotherapy. However, low metabolic stability of conventional STING agonists limits their clinical application. Recent study shows that chemotherapeutic drugs cisplatin and camptothecin (CPT) can activate cGAS-STING pathway and induce immune response by DNA damage. Nevertheless, the ability of chemotherapeutic drugs to activate STING is so weak that new strategies are required to improve drug delivery efficiency for enhanced DNA damage, and then efficiently activate cGAS-STING pathway. Herein, we have developed a hybrid platinum prodrug (CPT-Pt (IV)) which can be triggered to release cisplatin and CPT in tumor cells. CPT-Pt (IV) with high hydrophobicity is further self-assembled with a ROS sensitive polymer (P1) and mPEG2k-DSPE into ROS responsive nanoparticles (NPs). NPs could accumulate in the tumor site to release cisplatin and CPT, resulting in DNA double damage and finally activating cGAS-STING pathway, inducing DC cells maturation and increasing tumor infiltration of CD8+ T cells on colorectal cancer mouse model. This study showed that common DNA targeted drugs can activate the cGAS-STING pathway in situ via nano delivery system, and enhance the effect of chemotherapy and immunotherapy, which provide a new strategy for clinical antitumor therapy.
Assessment of the genetic and clinical determinants of hip fracture risk: Genome-wide association and Mendelian randomization study
Authors: Maria Nethander, Eivind Coward, Ene Reimann, Louise Grahnemo, Maiken E. Gabrielsen, Carl Wibom, Reedik Mägi, Thomas Funck-Brentano, Mari Hoff, Arnulf Langhammer, Ulrika Pettersson-Kymmer, Kristian Hveem, Claes Ohlsson, Mari Nelis, Lili Milani, Tõnu Esko, Andres Metspalu
Journal: Cell Reports Medicine (2022)

Hip fracture is the clinically most important fracture, but the genetic architecture of hip fracture is unclear. Here, we perform a large-scale hip fracture genome-wide association study meta-analysis and Mendelian randomization study using five cohorts from European biobanks. The results show that five genetic signals associate with hip fractures. Among these, one signal associates with falls, but not with bone mineral density (BMD), while four signals are in loci known to be involved in bone biology. Mendelian randomization analyses demonstrate a strong causal effect of decreased femoral neck BMD and moderate causal effects of Alzheimer's disease and having ever smoked regularly on risk of hip fractures. The substantial causal effect of decreased femoral neck BMD on hip fractures in both young and old subjects and in both men and women supports the use of change in femoral neck BMD as a surrogate outcome for hip fractures in clinical trials.
Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant
Authors: Olivier Demaria, Laurent Gauthier, Marie Vetizou, Audrey Blanchard Alvarez, Constance Vagne, Guillaume Habif, Luciana Batista, William Baron, Nourhène Belaïd, Mathilde Girard-Madoux, Cedric Cesari, Melody Caratini, Frédéric Bosco, Olivier Benac, Julie Lopez, Aurore Fenis, Justine Galluso, Sylvia Trichard, Barbara Carrette, Florent Carrette, Aurélie Maguer, Solène Jaubert, Audrey Sansaloni, Robin Letay-Drouet, Camille Kosthowa, Naouel Lovera, Arnaud Dujardin, Fabien Chanuc, Mélanie Le Van, Sivan Bokobza, Nicolas Jarmuzynski, Camille Fos, Nicolas Gourdin, Romain Remark, Eric Lechevallier, Nicolas Fakhry, Sébastien Salas, Jean-Laurent Deville, Roger Le Grand, Cécile Bonnafous, Lukas Vollmy, Agnès Represa, Sabrina Carpentier, Benjamin Rossi, Ariane Morel, Stéphanie Cornen, Ivan Perrot, Yannis Morel, Eric Vivier
Journal: Cell Reports Medicine (2022)

Harnessing innate immunity is emerging as a promising therapeutic approach in cancer. We report here the design of tetraspecific molecules engaging natural killer (NK) cell-activating receptors NKp46 and CD16a, the β-chain of the interleukin-2 receptor (IL-2R), and a tumor-associated antigen (TAA). In vitro, these tetraspecific antibody-based natural killer cell engager therapeutics (ANKETs) induce a preferential activation and proliferation of NK cells, and the binding to the targeted TAA triggers NK cell cytotoxicity and cytokine and chemokine production. In vivo, tetraspecific ANKETs induce NK cell proliferation and their accumulation at the tumor bed, as well as the control of local and disseminated tumors. Treatment of non-human primates with CD20-directed tetraspecific ANKET leads to CD20+ circulating B cell depletion, with minimal systemic cytokine release and no sign of toxicity. Tetraspecific ANKETs, thus, constitute a technological platform for harnessing NK cells as next-generation cancer immunotherapies.